title: Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure.
abstract: Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.
authors.affiliation: Department of Cardiology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany. dirk.westermann@web.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Olga
authors.initials: O
authors.lastname: Lettau
authors.forename: Anton
authors.initials: A
authors.lastname: Roks
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Felicitas
authors.initials: F
authors.lastname: Escher
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology; D005650:Fumarates / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000150:complications / Q000188:drug therapy*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D003094:Collagen; D005650:Fumarates; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D012083:Renin; D019715:Tissue Inhibitor of Metalloproteinase-1; D000092502:Renin Inhibitors; C446481:aliskiren